The Future of Triple-Negative Breast Cancer Treatment Includes Immunotherapy Combinations

Up-and-coming treatments for patients with triple-negative breast cancer (TNBC) may include immunotherapy combinations, according to Sylvia Adams, M.D.

BY Angelica Welch

PUBLISHED September 06, 2017

Sylvia Adams, MD

Up-and-coming treatments for patients with triple-negative breast cancer (TNBC) may include immunotherapy combinations, according to Sylvia Adams, M.D.

Single-agent immunotherapy has demonstrated a modest clinical response in pretreated patients. The findings of the phase 2 KEYNOTE-086 trial showed that Keytruda (pembrolizumab) had antitumor activity in patients with heavily pretreated metastatic TNBC, with an overall response rate of 4.7 percent as a single agent.

Additionally, Tecentriq (atezolizumab) monotherapy has been explored in women with metastatic TNBC in the frontline and pretreated setting. In a phase 1 trial, the two-year overall survival rate of 47 percent in the frontline setting.

Immunotherapy is also making an impact in metaplastic breast cancer, and the subtype is now included as an arm in the SWOG DART trial.

In an interview with CURE, Adams, associate professor, Department of Medicine, director, Clinical Research, Breast Cancer Disease Management Group, NYU Langone Medical Center, discussed her presentation on immunotherapy updates in TNBC, as well as ongoing clinical trials that could change the treatment paradigm.

What progress is being seen with combinations with immunotherapy in TNBC?

Combining immunotherapy with other targeted therapies, such as chemotherapies and radiation treatments, is probably going to be the future of breast cancer. [This is] because the response rate to single-agent immunotherapy remains low, especially in pretreated patients. Although in the frontline setting — the women who have been newly diagnosed with metastatic breast cancer — we see significant numbers of patients respond. The findings show that this response can be durable and can impact their outcome and survival. This is very, very important for TNBC because, currently, the standard of care is chemotherapy, which does not typically provide durable responses and comes with significant toxicities.

You spoke about a case of metaplastic breast cancer in a recent presentation. Could you discuss the work being done in that subtype?

In metaplastic breast cancer, we have seen an incredible response to immunotherapy in a woman who has recurrent disease with large-volume chest wall involvement and a lung metastasis. She had been refractory to several chemotherapies, so this is very exciting because it is one of the chemo-refractory, very poor prognosis subtypes of breast cancer.

After this observation, there have also been studies that specifically look at PD-1 and PD-L1 expression in these tumors. Due to that finding that most of those cancers express the target for immunotherapy, we are very excited to actually include an arm for metaplastic breast cancer in the ongoing National Cancer Institute-sponsored DART trial, which combines two immunotherapies — Yervoy (ipilimumab) and Opdivo (nivolumab) — for rare tumor types. This will be arm number 36, and this trial is open in 600 locations across the United States. We hope that this will provide access to patients with this rare subtype of breast cancer.

Are there any other ongoing trials that look particularly promising?

At NYU Langone Medical Center, we have an investigator-initiated study of Keytruda with Abraxane (nab-paclitaxel) for women who have TNBC but also [for women who have] hormone receptor–positive disease, for which there are very few immunotherapy trials.

There are also randomized phase 3 studies of neoadjuvant immunotherapy with chemotherapy. There is a large study that is looking at frontline treatment in women with metastatic TNBC.

Excitingly, we finished accrual to IMpassion130, which is a very large trial that was designed to get FDA registration, if positive. In this trial, women with metastatic TNBC are randomized to frontline backbone chemotherapy of nab-paclitaxel plus or minus Tecentriq (atezolizumab), to see if it affects responses to therapy, outcomes, and survival. There are multiple trials in this country and I would refer patients to clinical trials.

Would you say that immunotherapy has the biggest potential in TNBC of all breast cancer subtypes?

TNBC is the primary subtype in which it will be useful. Studies that were presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting showed significant improvement in achieving a response in the neoadjuvant setting. There will be many more studies coming in the next year that look at how to combine immunotherapy with standard therapy in this setting, and how to sequence it with the current chemotherapeutics.

What are the recent updates with Keytruda in the neoadjuvant setting?
The I-SPY trial was designed to look at new agents and to see whether there were any promising early signals so that they could graduate into larger randomized studies. The I-SPY 2 trial showed that the response is significantly improved if you add Keytruda to standard neoadjuvant chemotherapy.

What do you believe is the most significant challenge for immunotherapy in breast cancer?

Increasing the response rate is the biggest challenge at this time. Single-agent activity in women who have been pretreated are in the single-digit range. Whereas, in the frontline setting, we have about 23 percent of patients achieve responses. Therefore, in the second-line and beyond settings, we need to find better combinations.